Paul Szabolcs, M.D.
Campus: 4401 Penn Avenue
Office: Rangos Room 5125
Pittsburgh, PA 15224
- Professor, Department of Pediatrics
- Professor, Department of Immunology
My laboratory has a long-standing interest to understand the development of immune competence, in particular T cell immunity, in recipients of allogeneic hematopoietic cell transplantation (HCT). Our research bridges the gap between the bench and the clinic with the overall goal of developing novel strategies to accurately diagnose, predict, and therapeutically accelerate post transplant immune reconstitution without increasing graft versus host disease (GvHD). For many years we have focused on unrelated cord blood transplantation (UCBT) in children as the dominant clinical scenario and laboratory model. Remarkably, despite the HLA-mismatched setting, the antigen inexperienced naïve T cells removed from the immunologically biased fetal-maternal interface will eventually offer protective immunity from viral and opportunistic infections despite ongoing immunosuppression for months after transplant. We were the first to demonstrate the feasibility to in vitro prime cord blood T cells against cytomegalovirus, a significant pathogen. Subsequently, we identified the biological requirements and demonstrated the feasibility to simultaneously expand and induce ex vivo maturation of cord blood T lymphocytes to reach a critical maturational stage in Th1/Tc1 function that can render them receptive to further in vitro priming strategies to generate cytotoxic T lymphocytes (CTL) against human leukemia. Our translational research programs have received support from NCI, NHLBI, and NIAID.
Current work at the University of Pittsburgh:
- We are testing and developing strategies to overcome barriers of immune ignorance and hypo-responsiveness in patients with acute myeloid leukemia by developing autologous or cord blood donor derived T cell based polyclonal T cell immunotherapy strategies.
- Mechanistic studies of immune competence and tolerance in human transplantation. We have ongoing experiments probing:
- how tolerance will develop in UCBT recipients permitting eventual withdrawal of all immunosuppressive drugs within the first year after transplantation. We are actively probing the role of central deletional mechanism besides peripheral regulatory networks.
- how immune competence and tolerance will develop following tandem solid organ and T cell-depleted bone marrow transplantations from the same unrelated HLA-mismatched cadaveric donor. These patients suffer from pulmonary and infectious complications of a variety of primary immune deficiency diseases (PID). In 2009, we were the first to demonstrate the feasibility and success of this strategy in humans when a teenager with Artemis deficient SCID has become immune competent with donor lymphocytes. In vitro hyporeactivity was maintained after Treg depletion and was independent of IL-10 secretion, supporting the notion of clonal deletion as thymocytes of donor origin developed in the multiply HLA-mismatched host thymus. While the University of Pittsburgh is the only center with an active clinical trial to offer hope for PID patients with advanced lung disease, we have designed laboratory experiments to analyze global and mucosal immune competence and to identify the mechanism for recipient-specific hypo-responsiveness in accrued patients. This is a collaborative research program with other members of the Department of Immunology and the Starzl Institute as we probe the acquisition of cadaveric donor-derived mucosal immunity in heavily infected patients while investigating in parallel the alloreactive milieu at the lung mucosal interface.
Szabolcs P, Buckley R, Davis R, Moffet J, Voynow J, Jeyaraj A, Chen X, Sempowski G, Zaas D. Tolerance After Lung and Bone Marrow Transplantation from an Unrelated Cadaveric Donor. Journal of Allergy and Clinical Immunology, 2015 Feb;135 (2):567-70.
Parikh SH, Mendizabal A, Benjamin CL, Komanduri KV, Antony J, Petrovic A, Hale G, Driscoll TA, Martin PL, Page KM, Flickinger K, Moffet J, Niedzwiecki, D, Kurtzberg, J, Szabolcs P. A Novel Reduced-Intensity Conditioning Regimen for Unrelated Umbilical Cord Blood Transplantation in Children with Nonmalignant Diseases. Biol Blood Marrow Transplant. 2014 Mar;20(3):326-36, PMID: 24296492
Davis CC, Marti L, Sempowski G, Jeyaraj DA, Szabolcs P. IL-7 permits Th1/Tc1 maturation of cord blood T cells while enhances ex vivo expansion in collaboration with CD3/CD28 costimulatory beads and Il-2: A critical step towards adoptive immunotherapy. Cancer Research, 2010 Jul 1;70(13):5249
Mazur AM, Davis CC, and Szabolcs P. Ex vivo expansion and Th1/Tc1 maturation of umbilical cord blood T cells by CD3/CD28 costimulation. Biol. Blood and Marrow Transplantation, 2008 Oct;14(10):1190-6. PMID: 18804050
Szabolcs P and Niedzwiecki, D. Immune reconstitution after unrelated cord blood transplantation. Cytotherapy, 2007, 9(2):111-122
Park KD, Marti L, Kurtzberg J, Szabolcs P. In vitro priming and expansion of Cytomegalovirus-specific Th1 and Tc1 T cells from naïve cord blood lymphocytes. Blood, 2006 Sep 1, 108(5):1770.
Szabolcs P, Park KD, Marti L, Deoliveira D, Lee Y, Colvin MO, Kurtzberg J. Superior depletion of alloreactive T cells from PBSC and umbilical cord blood grafts by the combined use of trimetrexate and IL-2 immunotoxin. Biol. Blood and Marrow Transplantation, 2004; 10:772-783. PMID: 15505608
Szabolcs P, Park KD, Reese M., Marti L, Broadwater G, Kurtzberg J. Coexistent naïve phenotype and higher cycling rate of cord blood T cells as compared to adult peripheral blood. Experimental Hematology, 2003 Aug;31(8):708-14.
Szabolcs P, Park KD, Reese M., Marti L., Broadwater G., Kurtzberg J. Absolute values of dendritic cell subsets in bone marrow, cord blood, and peripheral blood enumerated by a novel method. Stem Cells, 2003;21:296-303.
Szabolcs P, Gallardo HF, Ciocon DH, Sadelain M, Young, JW. Retrovirally transduced human dendritic cells retain a normal phenotype and potent T cell stimulatory capacity. Blood 1997; 90:2160. PMID: 9310466
Szabolcs P, Avigan D, Gezelter S, Ciocon DH, Moore MAS, Steinman RMS, Young JW. Dendritic cells and macrophages can mature independently from a human bone marrow-derived, post-CFU intermediate. Blood 1996; 87:4520-4530. PMID: 8639819
Szabolcs P, Moore MAS, Young JW. Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow progenitors by c-kit-ligand, GM-CSF, and TNFa. J Immunol 1995; 154:5851-5861. PMID: 7538534